JP2020196755A - Compositions comprising combinations of organic acids - Google Patents

Abstract

To provide compositions comprising combinations of organic acids and methods of using the same.SOLUTION: The invention provides a composition for use in a method of disrupting a biofilm, the method comprising applying the composition to a surface having the biofilm. The composition comprising succinic acid, aconitic acid and a carrier, where the succinic acid and aconitic acid are present in the composition in a ratio of succinic acid to aconitic acid from 0.9:1 to about 14:1. The surface is a surface of the oral cavity. The surface of the oral cavity is selected from the group consisting of surfaces of one or more teeth, surfaces of the gums, and combinations of two or more thereof. The composition is applied to the surface in the form of a mouthwash or mouthrinse.SELECTED DRAWING: None

Description

The present invention relates to compositions containing a combination of organic acids and their use. In certain embodiments, the present invention relates to compositions comprising a combination of succinic acid and aconitic acid and the use of such compositions to inhibit biofilms.

Organic acids and their combinations have been recognized for use in a wide variety of compositions, including compositions for oral care. For example, WO 2012/001347 describes extracts from shiitake mushrooms, chicory, and / or raspberries, and oral health compositions containing low molar mass fractions derived from these extracts. These compositions described contain or contain one or more of the following compounds: quinic acid, adenosine, inosine, trans-aconitic acid, cis-aconitic acid, oxalic acid, adenosine, and succinic acid. This can be added. Although this reference claims the antibiofilm action of the composition by multiple mechanisms of action, there is no disclosure of the unexpected effects resulting from the particular combination of the above compounds.

Applicants can combine certain combinations of organic acids to prepare compositions that tend to have significant and unexpected effects, including high biofilm inhibition. It was discovered unexpectedly.

In certain embodiments, the present invention is a composition comprising succinic acid, aconitic acid, and a carrier in which succinic acid and aconitic acid are present in a ratio of about 0.9: 1 to about 40: 1. Regarding the composition.

According to certain other embodiments, the present invention relates to a method of inhibiting a biofilm, comprising applying the composition of the invention described in the claims to a surface having the biofilm.

According to certain other embodiments, the present invention relates to a method of removing a biofilm from a surface, comprising applying the composition of the invention described in the claims to a surface having the biofilm.

According to certain other embodiments, the present invention relates to a method of reducing bacterial adhesion to a surface, comprising applying the composition of the invention described in the claims to the surface.

Formulations containing succinic acid (SA) and aconitic acid (AA) in different ratios at a total concentration of 21 mM (0.25-0.37 wt% depending on the ratio of SA to AA, see Table 7) It is the figure which plotted the removal rate (%) (with respect to water) of a biofilm after a plurality of treatments with respect to the reduction rate (%) (with respect to water) of bacterial adhesion. Different ratios of succinic acid (SA) and aconitic acid (AA) at a total concentration of 21 mM (0.25 to 0.37% by weight, depending on the ratio of SA to AA, see Table 7) (with the ratio in FIG. 1). It is a figure which plotted the removal rate (%) (with respect to water) of a biofilm after a plurality of treatments with respect to the reduction rate (%) (with respect to water) of bacterial adhesion for the formulation containing with (different).

Unless otherwise stated, all percentages described herein are solid / active ingredient weight percentages.

As mentioned above, Applicants expect that compositions containing both succinic acid and aconitic acid combinations in their carriers will tend to show significant effects compared to other organic acid combinations. I found it without doing it. In particular, in certain embodiments, Applicants have found that such compositions exhibit a marked increase in the inhibitory properties of biofilms. More specifically, as described herein below and also shown in the tables and drawings, Applicants found that the combination of succinic acid and aconitic acid compared to the combination of other organic acids ( It was found that a) the biofilm removal rate (%) and (b) the bacterial adhesion reduction rate (%) both tended to show a remarkable increase. Applicants point out that as used herein, "inhibiting a biofilm" refers to the removal of the biofilm from the surface, reduced bacterial adhesion to the surface, or both. I will do it.

In the present invention, any suitable succinic acid can be used. Butanedioic acid, which is the strain name of IUPAC, or succinic acid, which is also known as the historical name spirit of amber, has the chemical formula C ₄ H ₆ O ₄ and the structural formula HOOC- (CH ₂ ) _2- COOH. It is a two-base dicarboxylic acid represented. The succinic acid used herein may be of natural or synthetic origin. In certain embodiments, succinic acid is of synthetic origin. Commercially available sources of succinic acid include Acros Organics, Alfa Aesar, Fisher Chemical, Fluka, MP Biomedicals, Sigma Aldrich, Specrum Chemicals, and TCI Fine Chemicals.

Any suitable aconitic acid can be used in the present invention. Prop-1-ene-1,2,3-tricarboxylic acid, which is the strain name of IUPAC, or Achilleic acid, Equisetic acid, Citridinic acid, or pyrocitrate as historical names. Aconitic acid, also known as (Pyrocitric acid), is represented by the chemical formula C ₆ H ₆ O ₆ and the structural formula HO ₂ CCH = C (CO ₂ H) CH ₂ CO ₂ H, cis-aconitic acid and trans-aconitic acid. It is an organic acid having two isomers of. In certain embodiments, trans-aconitic acid is used. In other embodiments, cis-aconitic acid is used. The aconitic acid used herein may be of natural or synthetic origin. In certain embodiments, the aconitic acid is of synthetic origin. Commercially available sources of succinic acid include Alfa Aesar, Fluka, MP Biomedicals, Parchem Fine & Specialty Chemicals, Sigma Aldrich, Spectrum Chemicals, and TCI Chemicals.

Any suitable amount and ratio of succinic acid and aconitic acid can be used in the composition of the present invention. As will be appreciated by those skilled in the art, based on their respective pKa values, the succinic acid and aconitic acid used in the present invention are in equilibrium with their respective salt morphologies at most pH. Thus, all amounts and ratios of succinic acid and aconitic acid described and claimed herein refer to the total amount of such acids in a particular composition in both acid and salt forms. For example, in a composition containing 0.2% by weight of succinic acid, the total amount of solid / active succinic acid in the form of acid and salt is 0.2% by weight based on the total weight of the composition. In compositions where the total weight of succinic acid and trans-aconitic acid is 1% by weight, succinic acid in the form of acid and salt and trans-aconitic acid in the form of acid and salt are combined relative to the total weight of the composition. The total amount of solid / active ingredient is 1% by weight.

In certain embodiments, succinic acid and aconitic acid are effective in preventing and inhibiting the formation of biofilms in the oral cavity in the composition, and the composition is stable in such amounts. Exists by weighing. Generally, the composition comprises succinic acid and aconitic acid in a total weight of about 0.1 to about 2% by weight based on the total weight (w / w%) of the composition. In certain embodiments, the total weight of succinic acid and aconitic acid is about 0.1 to about 1% by weight of the composition, or about 0.1 to about 0.9% by weight of the composition, or the composition. About 0.1 to about 0.5% by weight, or about 0.1 to about 0.3% by weight of the composition. In certain embodiments, the total weight of succinic acid and aconitic acid contained in the composition is from about 0.13% by weight to about 0.89% by weight of the composition and from about 0.13% by weight to about 0.13% by weight of the composition. It is 0.52% by weight, or about 0.13% by weight to about 0.3% by weight of the composition.

Generally, the ratio of succinic acid to aconitic acid (succinic acid: aconitic acid) in the composition of the present invention is about 0.9: 1 to about 40: 1. In certain embodiments, the ratio of succinic acid to aconitic acid is about 0.9: 1 to about 20: 1, or about 0.9: 1 to about 14: 1, or about 0.9: 1 to about. 9: 1, or about 0.9: 1 to about 6: 1, or about 0.9: 1 to about 4: 1. In certain embodiments, the ratio of succinic acid to aconitic acid is about 1.1: 1 to about 20: 1, or about 2.5: 1 to about 20: 1, or about 6: 1 to about 20 :. 1, or about 1.1: 1 to about 14: 1, or about 2.5: 1 to about 14: 1, or about 6: 1 to about 14: 1, or about 1.1: 1 to about 9: 1, or about 2.5: 1 to about 9: 1, or about 6: 1 to about 9: 1. In certain embodiments, the ratio of succinic acid to aconitic acid is about 1.3: 1 to about 20: 1, or about 1.3: 1 to about 13: 1, or about 1.3: 1 to about. 8.33: 1, or about 1.3: 1 to about 6: 1, or about 2.5: 1 to about 13: 1, or about 2.5: 1 to about 8.33: 1, or about 2. .5: 1 to about 6: 1, or about 6: 1 to about 8.33: 1, or about 4: 1 to about 5.5: 1. In certain preferred embodiments, the ratio of succinic acid to aconitic acid is about 0.9: 1 to about 14: 1.

Any of the various solvents allowed in the oral cavity can be used in the compositions of the present invention. The solvent can be aqueous or non-aqueous. The aqueous solvent is generally water, but water / alcohol mixtures can also be used. In certain embodiments, water is added to the composition as "q.s." (Quantum Sufficit (Latin for "as much as needed")). In certain embodiments, the aqueous phase comprises from about 60% to about 95% by weight, or from about 75% to about 90% by weight of the composition. In certain compositions, water is present in an amount of about 60% to about 95%, or about 75% to about 90%. The compositions of the present invention may also be formulated in the form of dry powders, chewing gum, films, semi-solid, solid or liquid concentrates. In such embodiments, for example, in the case of liquid concentrates or powder formulations, water is added in appropriate amounts as needed, or by removing water using standard evaporation methods well known in the art. It is also possible to produce a composition in the form of a dry powder. The evaporated or lyophilized form is convenient for storage and shipping.

In some embodiments, alcohol can be added to the composition. Any of the various alcohols represented by the formula R _3- OH (where R ₃ is an alkyl group having 2 to 6 carbons) can be used in the present invention. Examples of suitable alcohols of formula R ₃ -OH, ethanol, n- propanol, isopropanol, butanol, pentanol, hexanol, and the like combinations of the two or more of these. In certain embodiments, the alcohol is ethanol or comprises ethanol.

In some embodiments, the alcohol is in the composition at about 10.0% by volume or more of the total composition, or about 10.0% by volume to about 35.0% by volume of the total composition, or the total composition. It may be present in an amount of about 15.0% to about 30.0% by volume and may be from about 20.0% to about 25.0% by volume of the total composition.

In some embodiments, the composition can include a low concentration of alcohol. The phrase "low concentration" alcohol means that the amount of R _3- OH alcohol is about 10% by volume or less, or about 5% by volume or less, or about 1.0% by volume or less, or about 0 of the total composition. It means that it is 1% by volume or less. In certain embodiments, the compositions of the present invention are free of R _3- OH alcohols.

The pH of the composition of the present invention is preferably less than 7. In certain embodiments, the pH of the composition is less than about 3-7, or about 3.5-7, or about 3.5-about 6.5, or about 3.5-about 5.5, or. It is about 3.5 to about 5.

As will be appreciated by those skilled in the art, the pH of the composition can be adjusted or achieved with an amount of buffer effective to bring the composition to a pH below 7. The composition may optionally contain at least one pH modifier, of which the acidifying agents for lowering the pH, the basicizing agents for raising the pH, and those useful herein are. Buffering agents for adjusting the pH to the desired range can be mentioned. For example, by adding one or more compounds selected from acidifying agents, basicizing agents, and buffering agents, the pH is adjusted to about 2 to about 7, or in different embodiments from about 3 to about 6, or about 4 to. It can be about 5. Carboxylic and sulfonic acids, acid salts (eg monosodium citrate, disodium citrate, monosodium malate), alkali metal hydroxides such as sodium hydroxide, borates, silicates , Imidazole, and any mixture thereof, which is acceptable in the oral cavity, can be used. One or more pH modifiers may optionally be present in total amounts effective in keeping the composition in the acceptable pH range in the oral cavity. In certain embodiments, the inorganic acid can be used as a buffer added to the composition.

In certain embodiments, the organic acid can be used as a buffer added to the composition. Organic acids suitable for use in the compositions of the present invention are, but are not limited to, ascorbic acid, sorbic acid, citric acid, glycolic acid, lactic acid and acetic acid, benzoic acid, salicylic acid, phthalic acid, phenol. Sulphonic acids, and mixtures thereof, may be mentioned, optionally the organic acid is selected from the group consisting of benzoic acid, sorbic acid, citric acid and mixtures thereof, or optionally the organic acid is benzoic acid. ..

Generally, the amount of acidic buffer is from about 0.001% (or about 0.001% by weight) to about 5.0% (or about 5.0% by weight) of the composition. In certain embodiments, the organic acidic buffer is 0.001% (or about 0.001% by weight) to 1.0% by weight (or about 1.0% by weight) of the composition, or composition. It is present in an amount of about 0.100% (or about 0.100% by weight) to about 1.0% (or about 1.0% by weight).

The compositions of the present invention are, but are not limited to, oily ingredients, active ingredients, additional surfactants, wetting agents, solvents, flavoring agents, sweeteners, colorants, preservatives, pH adjusters, Any of a variety of optional components, such as pH buffers, may be further included.

Any of the various oily ingredients can be used in the compositions of the present invention. The oily component can include any one or more oils, or other water-insoluble or nearly water-insoluble substances. Almost water-insoluble means that its solubility in water at 25 ° C. is less than about 1% by weight, or optionally less than about 0.1% by weight. In certain embodiments, the oily component of the invention is at least one essential oil, a concentrated hydrophobic substance of natural or synthetic (or combination thereof) that generally comprises volatile compounds. Contains, is basically composed of, or is composed of a variety of flavor oils, or combinations of two or more of them. Examples of suitable essential oils, flavor oils, and their amounts are given below. In certain embodiments, the composition comprises a total amount of oily components of about 0.05% by weight or more, about 0.1% by weight or more, or about 0.2% by weight or more.

In certain embodiments, the compositions of the present invention comprise essential oils. Essential oils are volatile aromatic oils that may be synthesized or obtained from plants by distillation, squeezing, or extraction and usually give the aroma or flavor of the plants from which they are obtained. Have. Useful essential oils can provide bactericidal activity. Some of these essential oils also act as flavoring agents. Useful essential oils include, but are not limited to, citron, thymol, menthol, methyl salicylate (winter green oil), eucalyptor, carbachlor, camphor, anetol, carboxylic, eugenol, isoeugenol, limonene, Osimen, n-decyl alcohol, citronel, a-salpineol, methyl acetate, citronella acetate, methyl eugenol, thymolol, linalool, ethyllinaraol, saflora vanillin, spare mint oil, peppermint oil, lemon oil, orange oil, sage oil , Rosemary oil, katsura oil, piment oil, laurel oil, odorous oil, gerianol, velvenone, anis oil, bay oil, benzaldehyde, bergamot oil, bitter peach, chlorothymol, katsura aldehyde, citronella oil, clove oil, coal tar, Troporone derivatives such as eucalyptus oil, guayacol, hinokithiol, lavender oil, mustard oil, phenol, phenyl salicylate, pine oil, pine needle oil, sassafras oil, spike lavender oil, strax, thyme oil, truvalsum, televisionn oil, clove oil , And combinations thereof.

In certain embodiments, the essential oils are thymol ((CH ₃ ) ₂ CHC ₆ H ₃ (CH ₃ ) OH, also known as isopropyl-m-cresol), eucalyptus (C ₁₀ H ₁₈ O, also as cineole). (Known), menthol (CH ₃ C ₆ H ₉ (C ₃ H ₇ ) OH), also known as hexahydrothymol), methyl salicylate (C ₆ H ₄ OHCOOCH ₃ , also known as winter green oil), these It is selected from the group consisting of each isomer of the compound of the above, and a combination of two or more of these. In some embodiments, the compositions of the invention contain thymol. In some embodiments, the compositions of the invention contain menthol. In some embodiments, the composition contains all four of these essential oils.

In certain embodiments, Timor is used in an amount of about 0.0001% to about 0.6% by weight, or about 0.005% to about 0.07% by weight of the composition. In certain embodiments, eucalyptus is used in an amount of about 0.0001% to about 0.51% by weight, or about 0.0085% to about 0.10% by weight. In certain embodiments, menthol is used in an amount of about 0.0001% to about 0.25% by weight, or about 0.0035% to about 0.05% by weight of the composition. In certain embodiments, methyl salicylate is used in an amount of about 0.0001% to about 0.28% by weight, or about 0.004% to about 0.07% by weight of the composition. .. In certain embodiments, the total amount of all these essential oils present in the disclosed compositions is from about 0.0004% by weight to about 1.64% by weight, or about 0.0165% by weight by weight of the composition. It can be ~ about 0.49% by weight.

In certain embodiments, fluoride feed compounds may be present in the mouse rinse composition of the present invention. These compounds may be slightly water-soluble or completely water-soluble and are characterized by their ability to release fluoride or fluoride-containing ions into water. Common fluoride feed compounds are inorganic fluoride salts such as soluble alkali metals, alkaline earth metals and heavy metal salts, such as sodium fluoride, potassium fluoride, ammonium fluoride, cupric fluoride, fluoride. Zinc, stannic fluoride, tin fluoride, barium fluoride, sodium hexafluorosilicate, ammonium hexafluorosilicate, sodium fluorozirrate, sodium monofluorophosphate, mono- and aluminum difluorophosphate, and calcium fluorinated pyrophosphate. Includes sodium. Amin fluorides such as N'-octadecyltrimethylenediamine-N, N, N'-tris (2-ethanol) -hydrofluorate and 9-octadecenylamine hydrofluorate can also be used. .. In certain embodiments, the fluoride feed compound is up to about 5% by weight, or about 0.001% to about 2% by weight, or about 0.005% to about 1.5% by weight of the composition. It is generally present in sufficient amounts to release fluoride.

In certain embodiments, hypersensitivity relievers such as potassium salts of nitric acid and oxalic acid can be added to the present invention in an amount of 0.1% by volume to about 5.0% by volume of the composition. Other potassium-releasing compounds are also possible (eg KCl). High concentrations of calcium phosphate can also provide some additional relief of hypersensitivity. These substances are thought to act by forming obstructive surface mineral deposits on the tooth surface or by supplying potassium to the nerves inside the teeth to depolarize the nerves. A more detailed discussion of suitable hypersensitivity palliatives is incorporated herein by reference in its entirety, U.S. Patent Application Publication No. 2006/0013778 by Hodosh, and U.S. Pat. No. 6, by Markowitz et al. It can be found on Nos. 416 and 745.

In certain embodiments, compounds having a tartar-preventing effect (eg, various carboxylic acid salts, polyaspartic acid, etc.) can be added to the present invention. Further, an anionic polymer polycarboxylic acid salt is useful as a tartar preventive agent. Such substances are well known in the art and are used in the form of their free acids, or water-soluble alkali metal salts (eg, potassium and preferably sodium) or ammonium salts that are partially or preferably completely neutralized. Will be done. 1: 4 of maleic anhydride or maleic acid and another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (methoxyethylene) having a molecular weight (MW) of about 30,000 to about 1,000,000. Copolymers with a weight ratio of ~ 4: 1 are preferred. These copolymers are, for example, GAF Chemicals Corporation's Gantrez 25 AN139 (MW 500,000), AN119 (MW 250,000) and preferably S-97 pharmaceutical grade (MW 70,000). ) Is available.

Further dentin preventive agents include polyphosphoric acid (including pyrophosphate) and salts thereof; polyaminopropanesulfonic acid (AMPS) and salts thereof; polyolefin sulfonic acid and salts thereof; polyvinylphosphoric acid and salts thereof; polyolefin phosphoric acid and salts thereof. Diphosphonic acid and its salts; phosphonoalcancarboxylic acid and its salts; polyphosphonic acid and its salts; polyvinylphosphonic acid and its salts; polyolefin phosphonic acid and its salts; polypeptides; and mixtures thereof; carboxy-substituted polymers; And can be selected from the group consisting of mixtures thereof. In one embodiment, the salt is an alkali metal salt, or an ammonium salt. Polyphosphates are commonly used as fully or partially neutralized water-soluble alkali metal salts such as potassium salts, sodium salts, ammonium salts, and mixtures thereof. Examples of the inorganic polyphosphate include alkali metal (for example, sodium) tripolyphosphate, tetrapolyphosphate, dialkyl diacid metal (for example, disodium), trialkyl monoacid metal (for example, trisodium), potassium hydrogen phosphate, and phosphorus. Examples thereof include sodium hydrogen phosphate, alkali metal (eg, sodium) hexametaphosphate, and mixtures thereof. Polyphosphates larger than tetrapolyphosphates usually exist as amorphous vitreous materials. In one embodiment, the polyphosphate is produced by FMC Corporation, known by the trade names of Sodaphos (n = about 6), Hexaphos (n = about 13), and GlassH (n = about 21, sodium hexametaphosphate). And a mixture of these. Pyrophosphates useful in the present invention include alkali metal pyrophosphates, a few or monopotassium pyrophosphates or sodium salts, dialkali metal pyrophosphates, tetraalkali metal pyrophosphates, and mixtures thereof. Be done. In one embodiment, the pyrophosphates are disodium pyrophosphate, disodium dihydrogen pyrophosphate (Na ₂ H ₂ P ₂ O ₇ ), dipotassium pyrophosphate, tetrasodium pyrophosphate (Na ₄ P ₂ O ₇ ), It is selected from the group consisting of tetrapotassium pyrophosphate (K ₄ P ₂ O ₇ ) and mixtures thereof. Examples of the polyolefin sulfonic acid include those having an olefin group having two or more carbon atoms and salts thereof. Examples of the polyolefin phosphonic acid include those in which the olefin group has two or more carbon atoms. Examples of the polyvinyl phosphonic acid include polyvinyl phosphonic acid. Examples of diphosphonic acid and its salts include azocycloalkane-2,2-diphosphonic acid and its salts, azocycloalkane-2,2-diphosphonic acid and its salt ions, azacyclohexane-2,2-diphosphonic acid, and azacyclo. Pentan-2,2-diphosphonic acid, N-methyl-azacycloheptane-2,3-diphosphonic acid, EHDP (ethane-1-hydroxy-1,1,-diphosphonic acid), AHP (azacycloheptane-2,2) -Diphosphonic acid), ethane-1-amino-1,1-diphosphonate, dichloromethane diphosphonate and the like. Examples of the phosphonoalkanecarboxylic acid or the alkali metal salt thereof include PPTA (phosphonopropanetricarboxylic acid) and PBTA (phosphonobutane-1,2,4-tricarboxylic acid), which are acids or alkali metal salts, respectively. .. Examples of the polyolefin phosphonic acid include those in which the olefin group contains two or more carbon atoms. Examples of the polypeptide include polyaspartic acid and polyglutamic acid.

In certain embodiments, zinc salts such as zinc chloride, zinc acetate or zinc citrate, as a converging agent that gives a "disinfecting and cleaning" sensation, as a respiratory protection promoter, or as a tartar preventive, 0.0025 of the composition. It can be added in an amount of% by volume to 0.75% by volume by weight.

Any of the various additional surfactants can be used in the present invention. Suitable surfactants can include anionic, nonionic, cationic, amphoteric, zwitterionic surfactants, and combinations of two or more of these. Examples of suitable surfactants are disclosed, for example, in US Pat. No. 7,417,020 by Fevola, which is hereby incorporated by reference in its entirety.

In certain embodiments, the compositions of the invention comprise a nonionic surfactant. Any of one or more of the various nonionic surfactants of the art will have an alkylene oxide group (essentially hydrophilic) and an organic hydrophobic compound that may be essentially aliphatic or alkyl aromatic It will be recognized that it contains, but is not limited to, compounds produced by condensation with. Examples of suitable nonionic surfactants include, but are not limited to, alkyl polyglucosides; block copolymers such as alkyl glucose amines, copolymers of ethylene oxide and propylene oxide, eg Poloxamers; eg CRODURET (Croda). Ethoxylated hardened castor oil commercially available under the trade names of Inc., Edison, NJ); alkyl polyethylene oxides such as polysorbate and / or; fatty alcohol ethoxylates; polyethylene oxide condensates of alkylphenols; ethylene oxide, propylene oxide and ethylenediamine. Products induced by condensation with the reaction product with; ethylene oxide condensates of aliphatic alcohols; long chain tertiary amine oxides; long chain tertiary phosphine oxides; long chain dialkyl sulfoxides; and mixtures thereof.

An exemplary nonionic surfactant is selected from the group known as poly (oxyethylene) -poly (oxypropylene) block copolymers. Such copolymers are commercially known as poloxamers and are produced in a wide range of structures and molecular weights with different ethylene oxide contents. These nonionic poloxamers are non-toxic and are acceptable as direct food additives. These nonionic poloxamers are stable, easily dispersed in aqueous systems, and compatible with various formulations and other ingredients for oral formulations. These surfactants should have an HLB (hydrophilic lipophilic balance) of about 10 to about 30, preferably about 10 to about 25. As an example, as nonionic surfactants useful in the present invention, polymers 105, 108, 124, 184, 185, 188, 215, 217, 234, 235, 237, 238, 284, 288, 333, 334, Examples include poloxamers identified as 335, 338, 407, and combinations of two or more of these. In certain preferred embodiments, the composition comprises a poloxamer 407.

In certain embodiments, the composition of the claimed invention is less than about 9% nonionic surfactant, less than 5%, or less than 1.5%, or less than 1%, or less than 0.8%. , Less than 0.5%, less than 0.4%, or less than 0.3% nonionic surfactant. In certain embodiments, the compositions of the invention are free of nonionic surfactants.

In certain embodiments, the compositions of the invention also contain at least one alkyl sulfate ester surfactant. In certain embodiments, suitable alkyl sulfate surfactants are, but are not limited to, C _{8 to} C _{18 with} an even number of alkyl sulfate surfactants, and C ₁₀ to C in some cases. Sulfated C _{8 to} C ₁₈ , optionally sulfated C ₁₀ to, neutralized with a suitable basic salt such as sodium carbonate or sodium hydroxide and mixtures thereof to have a chain length of _16. alcohols having a carbon chain length of even-numbered C ₁₆ and the like. In certain embodiments, the alkyl sulfate ester salt is selected from the group consisting of sodium lauryl sulfate, sodium hexadecyl sulfate and mixtures thereof. In certain embodiments, a mixture of commercially available alkyl sulfates is used. The breakdown of the general ratio (%) of alkyl sulfates by alkyl chain length in commercially available sodium lauryl sulfate (SLS) is as follows.

In certain embodiments, the alkyl sulphate surfactant is from about 0.001% by volume to about 6.0% by volume of the composition, or optionally from about 0.1% by volume to about 0.5% by weight. It is present in the composition in an amount of% by volume.

Other suitable surfactants are those selected from the group consisting of sarcosine salt surfactants, isethionic acid surfactants, and taurine salt surfactants. Preferred for use herein are alkali metal or ammonium salts of these surfactants, such as: lauroyl sarcosine, myristol sarcosine, palmitoyl sarcosine, stearoyl sarcosine, and sarcosine acid. There are sodium and potassium salts of ole oil. The sarcosinate surfactant may be present in the compositions of the present invention in an amount of about 0.1% to about 2.5% by weight, or about 0.5% to about 2.0% by weight of the total composition. ..

As the bipolar ionic synthetic surfactant useful in the present invention, the aliphatic radical may be a straight chain or a branched chain, and one of the aliphatic substituents is about 8 to about 18 carbons. Derivatives of aliphatic quaternary ammonium, phosphonium, and sulfonium compounds having atoms and one having an anionic water solubilizing group such as a carboxy group, a sulfonate group, a sulfate group, a phosphate group, or a phosphonate group. Be done.

The amphoteric surfactant useful in the present invention is not limited to these, but the aliphatic radical may be a straight chain or a branched chain, and one of the aliphatic substituents is about 8 to. Aliphatic secondary and tertiary having about 18 carbon atoms, one having an anionic water solubilizing group such as a carboxylate group, a sulfonate group, a sulfate group, a phosphate group, or a phosphonate group. Examples include derivatives of amines. Examples of suitable amphoteric tenside agents are, but are not limited to, alkyliminodipropionates, alkylamphoglycinates (mono or di), alkylamphopropionates (mono or di), alkylamphos. Acetate (mono or di), N-alkyl [3-aminopropionic acid, alkylpolyaminocarboxylate, phosphorylated imidazoline, alkylbetaine, alkylamide betaine, alkylamidepropyl betaine, alkylsultaine, alkylamidesultaine, and their Examples include mixtures. In certain embodiments, the amphoteric surfactant is selected from the group consisting of alkylamide propyl betaine, anphoacetate such as sodium lauroamphoacetate, and mixtures thereof. A mixture of any of the above surfactants can be used. A more detailed discussion of anionic, nonionic and amphoteric surfactants can be found in US Pat. No. 7,087,650 granted to Lennon, US Pat. No. 7,084,104 granted to Martin et al., Sekiguchi. U.S. Pat. Nos. 5,190,747 granted to Gieske et al. And U.S. Pat. Nos. 4,051,234 granted to Gieske et al., Each of which is hereby referred to herein by reference in its entirety. It is to be used.

In certain embodiments, the composition of the claimed invention is less than about 9% amphoteric surfactant, less than 5%, or less than 1.5%, or less than 1%, or less than 0.8%, 0. Includes less than 5.5%, less than 0.4%, or less than 0.3% amphoteric surfactant. In certain embodiments, the compositions of the present invention are free of amphoteric surfactants.

Additional surfactants, along with alkyl sulphate detergents, can be added to aid in the solubilization of the essential oil, provided that the surfactant does not affect the bioavailability of the essential oil. Suitable examples include additional anionic surfactants, nonionic surfactants, amphoteric surfactants and mixtures thereof. However, in certain embodiments, the total surfactant concentration in the mouse rinse of the present invention, including the alkyl sulfate ester surfactant alone or in combination with other surfactants, is about 9 weight by weight of the composition. % Or less than about 9% by weight, and in some cases the total surfactant concentration is less than about 5% by weight, in some cases about 1% by weight or less, and in some cases about 0.5% by weight or less. Must be a surfactant.

In certain embodiments, sugar alcohols (wetting agents) are also added to the oral compositions of the present invention. The sugar alcohol solvent can be selected from the polyhydroxyfunctional compounds conventionally used in oral and ingestible products. In certain embodiments, the sugar alcohol needs to be a non-metabolic and non-fermentable sugar alcohol. In specific embodiments, the sugar alcohols include, but are not limited to, sorbitol, glycerol, xylitol, mannitol, maltitol, inositol, aritol, altritor, darsitol, galactitol, glucitol, hexitol, iditol, Examples include pentitol, ribitol, erythritol and mixtures thereof. If necessary, the sugar alcohol is selected from the group consisting of sorbitol and xylitol or mixtures thereof. In some embodiments, the sugar alcohol is sorbitol. In certain embodiments, the total amount of sugar alcohol added to effectively assist in the dispersion or dissolution of the mouse rinse or other ingredients should not exceed about 50% w / of the total composition. Alternatively, the total amount of sugar alcohol should not exceed about 30% by weight of the total composition. Alternatively, the total amount of sugar alcohol should not exceed 25% by weight by weight of the total composition. The sugar alcohol is about 1.0% by volume to about 24% by weight, or about 1.5% by volume to about 22% by weight, or about 2.5% by volume to about 20% by weight of the total composition. It can be an amount of%.

In certain embodiments, a polyol solvent is added to the composition. The polyol solvent is a polyhydric alkane (propylene glycol, glycerin, butylene glycol, hexylene glycol, 1,3-propanediol, etc.); a polyhydric alcan ester (dipropylene glycol, ethoxydiglycol); a polyalcan glycol (polyethylene glycol). , Polypropylene glycol, etc.) and polyols or polyhydric alcohols selected from the group consisting of mixtures thereof. In certain embodiments, the polyol solvent is 0% by volume to about 40% by volume, or about 0.5% to about 20% by volume, or about 1.0% to about 10% by volume. It may be present in an amount by volume% by weight.

In certain embodiments, the compositions of the invention have a pH of about 11 or less. In some embodiments, the composition has a pH of about 3 to about 7, or about 3.5 to about 6.5, or about 3.5 to about 5.0.

As will be appreciated by those skilled in the art, the pH of the composition can be adjusted or maintained with an amount of buffer effective in giving the composition a pH of 11 or less. The composition may optionally contain at least one pH modifier, of which the acidifying agents for lowering the pH, the basicizing agents for raising the pH, and those useful herein are. A buffering agent for maintaining the pH in a desired range can be mentioned. For example, by adding one or more compounds selected from acidifying agents, basicizing agents, and buffering agents, the pH is adjusted to about 2 to about 7, or in different embodiments from about 3 to about 6, or about 4 to. It can be about 5. Alkali metal hydroxides such as hydrochloric acid, carboxylic and sulfonic acids, acid salts (eg monosodium citrate, disodium citrate, monosodium malate monosodium malate), sodium hydroxide, borates, silicates. Any orally acceptable pH modifier can be used, including, without limitation, acid salts, imidazoles, and mixtures thereof. One or more pH modifiers may optionally be present in total amounts effective in keeping the composition in the acceptable pH range in the oral cavity. In certain embodiments, the inorganic acid can be used as a buffer added to the composition.

In certain embodiments, the organic acid can be used as a buffer added to the composition. Organic acids suitable for use in the compositions of the present invention are, but are not limited to, ascorbic acid, sorbic acid, citric acid, glycolic acid, lactic acid and acetic acid, benzoic acid, salicylic acid, phthalic acid, phenol. Sulphonic acids, and mixtures thereof, may be mentioned, optionally the organic acid is selected from the group consisting of benzoic acid, sorbic acid, citric acid and mixtures thereof, or optionally the organic acid is benzoic acid. ..

Generally, the amount of buffer compound is from about 0.001% to about 20.0% of the composition. In certain embodiments, the organic acid buffer is present in an amount of about 0.001% to about 10% by weight of the composition, or about 0.01% to about 1% of the composition.

In certain embodiments, conventional ingredients may be added in addition, such as mouthwashes and rinses of known techniques. Some alcohol-containing mouth rinses have a pH of about 7.0, but lowering the alcohol concentration requires the addition of acidic preservatives such as sorbic acid or benzoic acid to lower the pH level. May be. Therefore, a buffer system is further required to adjust the pH of the composition to the optimum level. Generally, the buffer system is realized by adding a weak acid and a salt thereof, or a weak base and a salt thereof. In some embodiments, an amount of 0.01% by volume (or about 0.01% by volume) to 1.0% by volume (or about 1.0% by volume) of the composition and sodium benzoate and Sodium citrate and citrate in an amount of 0.001% by volume (or about 0.001% by volume) to 1.0% by volume (or about 1.0% by volume) of the composition, as well as benzoic acid. Also, 0.01% (or about 0.01%) to 1.0% (or about 1.0%) amounts of phosphate and sodium / potassium phosphate by weight of the composition may be useful systems. Has been found. In certain embodiments, the buffer has a pH level of 3.0 (or about 3.0) to 8.0 (or about 8.0), optionally 3.5 (or about 3.5) to 6.5. (Or about 6.5), optionally added in an amount maintained at 3.5 (or about 3.5) to 5.0 (or about 5.0).

Further buffering agents include alkali metal hydroxides, ammonium hydroxide, organic ammonium compounds, carbonates, sesquicarbonates, borates, silicates, phosphates, imidazoles, and mixtures thereof. Specific buffers include monosodium phosphate, trisodium phosphate, sodium hydroxide, potassium hydroxide, alkali metal carbonate, sodium carbonate, imidazole, pyrophosphate, sodium gluconate, sodium lactate, and citrate. And sodium citrate.

Sweeteners such as aspartame, sodium saccharin (saccharin), sucralose, stevia, acesulfame K and the like can be added in an amount of about 0.0001% by volume to about 1.0% by volume to improve taste. In certain preferred embodiments, the sweetener comprises sucralose.

In certain embodiments, the composition comprises a flavoring agent or flavoring agent for the purpose of altering or enhancing the taste of the composition and for the purpose of reducing or masking the strong "stimulation" or "stickiness" of components such as thymol. Further included. Suitable flavoring agents include, but are not limited to, flavoring oils such as anise oil, anethole, benzyl alcohol, spearmint oil, citrus oil, vanillin and the like. Other flavoring agents such as citrus oil and vanillin may be added to provide further taste changes. In these embodiments, the amount of flavor oil added to the composition is from about 0.001% to about 5% by weight, or about 0.01% to about 0.3% by weight. You can. The particular flavoring or flavoring agent and other taste-improving ingredients used will vary depending on the particular taste and sensation desired. One of ordinary skill in the art can select and customize the types of these components to obtain the desired results.

In certain embodiments, approved food dyes can be used to give the compositions of the invention a preferred color. These can be selected from, but are not limited to, many acceptable food pigments. Examples of dyes suitable for this purpose include FD & C Yellow No. 5, FD & C Yellow No. 10, FD & C Blue No. 1, and FD & C Green No. 3. These dyes are in conventional amounts, generally about 0.00001% by weight to about 0.0008% by weight, or about 0.000035% by weight to about 0.0005% by weight, individually of the composition. Is added in.

Other conventional ingredients, including those well known and used in the art, may be used in the liquid or mouse rinse compositions of the present invention. Examples of these components include thickeners, suspending agents and softeners. Thickeners and suspending agents useful in the compositions of the present invention can be found in US Pat. No. 5,328,682 granted to Pullen et al., Which is hereby incorporated by reference in its entirety. it can. In certain embodiments, they are added in an amount of about 0.1% by weight to about 0.6% by weight, or about 0.5% by weight of the composition.

In some embodiments, antimicrobial preservatives can be added to the composition. Antimicrobial preservatives that can be used include, but are not limited to, cationic antibacterial agents, such as sodium benzoate, polyquaternium polycationic polymers (ie, polyquaternium-42: poly [oxy]. Ethylene (dimethylimino) ethylene (dimethylimino) ethylenedichloride]), quaternary ammonium salts or quaternary ammonium compounds, parabens (ie, esters of parahydroxybenzoate or parahydroxybenzoic acid), hydroxyacetophenone, 1, 2 -Hexanediol, caprylyl glycol, chlorohexidine, alexidine, hexetidine, benzalkonium chloride, domiphen bromide, cetylpyridinium chloride (CPC), tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC) , Octenidin, bisbiguanide, zinc or tin ion agents, grapefruit extracts, mixtures thereof. Other antibacterial or antimicrobial agents include, but are not limited to, 5-chloro-2- (2,4-dichlorophenoxy) -phenol, commonly referred to as triclosan; 8-hydroxyquinolin. And salts thereof, copper (II) compounds including, but not limited to, copper (II) chloride, copper (II) sulfate, copper (II) acetate, copper (II) fluoride, copper (II) hydroxide; phthalic acid. Phtalic acids and salts thereof, including but not limited to those disclosed in US Pat. No. 4,994,262, including, but not limited to, magnesium monopotassium phthalate; sanginalin; salicylanilide; iodine; sulfonamide; phenols. Delmopinol, octapinol, and other piperidino derivatives; niacin preparations; nystatin; apple extract, timole oil; timole; augmentin, amoxycillin, tetracycline, doxicycline, minocycline, metronidazole, neomycin, canamycin, cetylpyridinium chloride, and clindamycin, etc. Antibiotics; analogs and salts of the above; methyl salicylate; hydrogen peroxide; metal salts of chlorite; pyrrolidone ethyl cocoyl alginate; ethyllauroyl alginate monochloride hydrate; and all mixtures of the above. Can be mentioned. In another embodiment, the composition comprises a phenolic resin antimicrobial compound, and a mixture thereof. The antimicrobial component may be present in an amount of about 0.001% to about 20% by weight of the oral care composition. Another embodiment of the antimicrobial agent generally comprises from about 0.1% to about 5% by weight of the oral care composition of the present invention.

Other antibacterial agents may be basic amino acids and salts. In another embodiment, arginine may be included.

In certain embodiments, the composition can include whitening agents, oxidizing agents, anti-inflammatory agents, chelating agents, abrasives, combinations thereof, and the like.

A whitening agent can be added as an active ingredient in the composition. Active ingredients suitable for whitening are alkali metal peroxides and alkaline earth metal peroxides, chlorite metal salts, polyphosphates, perborates containing monohydrates and tetrahydrates, and hyperphosphorus. It is selected from the group consisting of acid salts, percarbonates, peroxyic acids, and persulfates such as ammonium persulfate, potassium persulfate, sodium persulfate, and lithium persulfate, and combinations thereof. Suitable peroxide compounds include hydrogen peroxide, urea peroxide, calcium peroxide, carbamide peroxide, magnesium peroxide, zinc peroxide, strontium peroxide, and mixtures thereof. In one embodiment, the peroxide compound is carbamide peroxide. Suitable metal chlorite salts include calcium chlorite, barium chlorate, magnesium chlorate, lithium chlorate, sodium chlorite, and potassium chlorite. Further whitening active ingredients can be hypochlorite and chlorine dioxide. In one embodiment, the chlorite is sodium chlorite. In another embodiment, the percarbonate is sodium percarbonate. In one embodiment, the persulfate is oxone. The concentration of these substances depends on the available oxygen or chlorine that the molecule can provide to bleach the stain, respectively. In one embodiment, the whitening agent is from about 0.01% to about 40% by weight of the oral care composition, from about 0.1% to about 20% by weight in another embodiment, from about 0% by weight in another embodiment. It may be present in a concentration of .5% to about 10% by weight, and in another embodiment from about 4% to about 7% by weight.

The composition of the present invention may contain an oxidizing agent such as a peroxide source. The peroxide source may include hydrogen peroxide, calcium peroxide, carbamide peroxide, or a mixture thereof. In some embodiments, the peroxide source is hydrogen peroxide. Other peroxide active substances include percarbonates, such as sodium percarbonate, which produce hydrogen peroxide when mixed with water. In certain embodiments, the peroxide source can be in the same phase as the tin ion source. In some embodiments, the composition comprises from about 0.01% to about 20% by weight of the peroxide source of the oral composition, in other embodiments from about 0.1% to about 5% by weight. %, In certain embodiments, from about 0.2% to about 3% by weight, and in another embodiment, from about 0.3% to about 2.0% by weight of peroxide source. Peroxide sources can be provided as free ions, salts, complexes, or capsules. It is desirable that the peroxide in the composition be stable. Peroxides can result in a reduction in stains as measured by the Cycling Stain Test, or other related method.

Anti-inflammatory agents may also be present in the compositions of the present invention. Such agents include, but are not limited to, oxicam nonsteroidal anti-inflammatory (NSAID) agents, salicylic acid salts, propionic acid, acetic acid, and fenamic acid. Such NSAIDs include, but are not limited to, ketorolac, fururubiprofen, ibuprofen, naproxen, indomethacin, diclofenac, etdrac, indomethacin, sulindac, tolmethin, ketoprofen, phenoprofen, pyroxycam, nabumetone, aspirin, Included are diclofenac, meclofenac acid, mephenamic acid, oxyphenbutazone, phenylbutazone, and acetaminophen. The use of NSAIDs such as ketorolac is claimed in US Pat. No. 5,626,838. The patent discloses a method for preventing and / or treating primary and recurrent squamous cell carcinoma of the oral cavity or oropharynx by topical administration of an effective amount of NSAID to the oral cavity or oropharynx. Suitable steroidal anti-inflammatory agents include corticosteroids such as fluosinolone and hydrocortisone.

The composition may optionally include chelating agents, also called sequestering agents, many of which also have tartar-preventing or sequestering activity. The use of chelating agents in oral care products is advantageous due to their ability to complex calcium as found in bacterial cell walls. Chelating agents can also break down plaque by removing calcium from calcium crosslinks that help maintain the plaque biomass in perfect condition. Chelating agents also have the ability to form complexes with metal ions, which helps prevent adverse effects of metal ions on product stability or appearance. Chelation of ions such as iron or copper helps delay the oxidative degradation of the final product. In addition, chelating agents can, in principle, remove stains by binding to the tooth surface, thereby replacing plastids or chromagens. By fixing these chelating agents, it is possible to prevent the occurrence of stains by destroying the binding sites of plastids on the tooth surface. Therefore, chelating agents can help reduce stains and improve detergency. The chelating agent can help improve the detergency by helping the chelating agent provide a chemical cleaning action, whereas the fused silica and the abrasive clean by a mechanical mechanism. Because fused silica is a good mechanical cleaner, more stains can be removed, thus retaining, suspending, or complexing stains so that the stains cannot stain the tooth surface again Chelating agents may be desirable. In addition, chelating agents can coat the tooth surface to help prevent new stains. It may be desirable to add the chelating agent to a formulation containing a cationic antibacterial agent. It may be desirable to add a chelating agent to the tin-containing formulation. Chelating agents can help stabilize tin and keep more tin bioavailable. The chelating agent can be used in tin formulations with a pH higher than about 4.0. In certain formulations, tin is more stable with fused silica as compared to precipitated silica and may therefore be stable without the use of chelating agents.

Suitable chelating agents include soluble phosphate compounds such as phytates with two or more phosphate groups and linear polyphosphates, including particularly tripolyphosphates, tetrapolyphosphates, and hexametaphosphates. Can be mentioned. Preferred polyphosphates have an average of about 6 to about 21 phosphate groups, such as those commercially known as Sodaphos (n≈6), Hexaphos (n≈13), and Glass H (n≈21). It has n. Other polyphosphate compounds can be added to or replaced with the above polyphosphates, in particular polyphosphate inositol compounds such as phytic acid, myoinositol pentax (dihydrogen phosphate); myoinositol tetrakis. (Dihydrogen phosphate), myoinositol trikis (dihydrogen phosphate), and alkali metal salts, alkaline earth metal salts, or ammonium salts thereof can be used. Phytic acid, also known herein as myo-inositol 1,2,3,4,5,6-hexakis (dihydrogen phosphate) or inositol hexaphosphate, and its alkali metal salts, alkaline earth metals. Salts or ammonium salts are preferred. As used herein, the term "phytate" includes phytic acid and salts thereof, as well as other polyphosphorylated inositol compounds. The amount of chelating agent in the composition depends on the chelating agent used and is generally at least about 0.1% to about 20%, preferably about 0.5% to about 10%, and More preferably, it is about 1.0% to about 7%.

Yet other phosphate compounds useful herein for their ability to bind, solubilize and transport calcium are as dentin enhancers, including organophosphate mono-, di-, or triesters. There are useful above-mentioned surface-active organophosphate compounds.

Other suitable agents with chelating properties for use in controlling plaque, tartar, and stains include US Pat. Nos. 3,678,154, White, Jr., granted to Wider et al. The polyphosphonates described in U.S. Pat. Nos. 5,338,537 granted to Zerby et al. And U.S. Pat. No. 5,451,401 granted to Zerby et al .; U.S. Pat. No. 3,737, granted to Francis. 533 Diphosphonates; US Pat. No. 4,847,070, granted July 11, 1989, granted to Pyrz et al., And April 28, 1987, granted to Benedit et al. Acrylic polymer or copolymer according to US Pat. No. 4,661,341; sodium alginate according to US Pat. No. 4,775,525 issued October 4, 1988, granted to Pera; granted to Pink et al. The polyvinylpyrrolidone described in British Patents 741,315, International Publication 99/12517, and US Pat. Nos. 5,538,714; and US Pat. Nos. 5,670,138 granted to Venema et al. No. and the copolymer of vinylpyrrolidone and carpoxylate described in JP-A-2000-063250 by Lion Co., Ltd.

Another chelating agent suitable for use in the present invention is an anionic polymer polycarboxylate. Such substances are well known in the art and are used in the form of their free acids, or water-soluble alkali metal salts (eg, potassium and preferably sodium) or ammonium salts that are partially or preferably completely neutralized. Will be done. Examples include maleic anhydride or maleic acid and another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether (methoxyethylene) having a molecular weight (MW) of about 30,000 to about 1,000,000. There are 1: 4 to 4: 1 copolymers of. These copolymers are, for example, GAF Chemicals Corporation's Gantrez® AN139 (MW500,000), AN119 (MW250,000) and S-97 Pharmaceutical Grades (MW70, It is available as 000). Other functional polymer polycarboxylates include maleic anhydride and 1: 1 copolymers of ethyl acetate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, or ethylene (the latter being EMA from, for example, Monsanto). (Available as No. 1103, MW 10,000 and EMA Grade 61), and acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether, or N-vinyl-2-pyrrolidone. 1: 1 copolymer of. Further functional polymer polycarboxylates are described in US Pat. No. 4,138,477 issued February 6, 1979, granted to Gaffar, and the US patent issued January 15, 1980 issued to Gaffar et al. Disclosed in Nos. 4,183,914, a copolymer of maleic anhydride with styrene, isobutylene, or ethyl vinyl ether; polyacrylic acid, polyitaconic acid, and polymaleic acid; and 1000 available as Universal ND-2. Includes moderately low molecular weight sulfoacrylic acid oligomers. Other suitable chelating agents include US Pat. No. 5,015,467 granted to Smitherman, and US Pat. No. 5,849,271 and US Pat. No. 5,622,689, both granted to Lucacovic. Polycarboxylic acids and salts thereof according to the item; for example, tartrate acid, citric acid, gluconic acid, malic acid; succinic acid, disuccinic acid, and those such as sodium or potassium gluconate and sodium citrate or potassium citrate. Salt; Citric acid / alkali metal citrate combination; Disodium tartrate; Dipotassium tartrate; Sodium potassium tartrate; Sodium hydrogen tartrate; Potassium hydrogen tartrate; Sodium tartrate monosuccinate, potassium tartrate dissuccinate acid or salt, and Examples thereof include mixtures thereof. In some embodiments, a mixture or combination of chelating agents may be present.

Abrasives suitable for use in the present invention include, but are not limited to, pumice, silica such as sand and quartz, powdered glass, silicon carbide, ilmenite (FeTIO ₃ ), zircon oxide, and zirconite silicate. , Topaz, TiO ₂ , aggregated lime, choke, pumice powder (flour of pumice), zeolite, talcum, kaolin, diatomaceous earth, aluminum oxide, silicate, zinc orthorate, sodium carbonate (boso), plastic particles, alumina, Alumina hydrate, calcium carbonate, calcium pyrophosphate, and mixtures thereof can be mentioned. The silica abrasive can be natural amorphous silica containing diatomaceous earth; or synthetic amorphous silica such as precipitated silica; or silica gel such as silica xerogel; or a mixture thereof.

In general, the amount of abrasive suitable for use in the compositions of the present invention is empirically determined to provide acceptable detergency and polishability according to methods well known in the art. In one embodiment, the composition of the invention comprises an abrasive. In one embodiment, the composition comprises a silica abrasive. In one embodiment, the silica abrasive is present in an amount of 0.001% to 30% by weight. In one embodiment, the silica abrasive is present in an amount of 1% to 15% by weight. In one embodiment, the silica abrasive is present in an amount of 4% to 10% by weight.

Other useful oral care active and / or inactive ingredients, and further examples thereof, are described in US Pat. No. 6,682,722 to Majeti et al. And US Pat. No. 6, to Nair et al. As can be seen in Nos. 121 and 315, the entire contents of each of these patents are incorporated herein by reference.

The compositions of the present invention can be produced by any of the various methods disclosed herein and well known in the art. In general, the compositions described will include any conventional mixing means well known in the art, such as by adding the desired components in a suitable container and mechanically stirring propellers, paddles, and the like. It can be prepared by mixing them under ambient conditions.

The compounds and compositions of the present invention can be used in a variety of ways to treat the mammalian body, specifically to inhibit biofilms on the surface of the oral cavity. According to certain embodiments, the invention includes inhibiting the biofilm on the surface by contacting the surface with the biofilm with the composition of the invention. In certain embodiments, the present invention comprises removing the biofilm from the surface by contacting the surface with the biofilm with the composition of the present invention. In certain embodiments, the invention comprises reducing bacterial adhesion to the surface by contacting the surface with the composition of the invention.

Based on the methods of the invention, any suitable surface of the oral cavity, including one or more tooth surfaces, gingival surfaces, one or more surfaces selected from the group consisting of combinations of two or more of these, etc. Can be contacted.

In each of the above methods, the composition of the claimed method can be introduced into the surface to be contacted by any of a variety of methods. In certain embodiments, the composition is introduced into the oral cavity by the user as a mouthwash or mouth rinse and applied to the surface. In certain embodiments, the composition is introduced into the oral cavity and applied to the surface as an article for brushing teeth, such as toothpaste on a toothbrush. The compositions of the present invention can be further introduced by mouth as gums, drops, soluble strips and the like and applied to the surface.

Further, the contacting step of the method of the present invention may include contacting the surface with the composition for any suitable length of time. In certain embodiments, the contacting step comprises contacting the surfaces for less than 30 seconds. In certain embodiments, the contacting step comprises contacting the surface with the composition for more than 30 seconds, such as about 30 seconds, about 40 seconds, about 1 minute, or longer than 1 minute.

Example 1: Biofilm preventive performance of compounds transcis-Aconitic acid, succinic acid, adenosine, quinic acid, inosin, shikimic acid, uridine, oxalic acid, or epicatechin, one of nine compounds, ethanol and benzo The formulations A1 to J1 shown in Table 1 were prepared by dissolving in an aqueous solution containing an acid buffer. Each of the nine formulations was tested in a biofilm preventive assay as described below.

Each formulation was used and the lid was treated by immersing a hydroxyapatite pegged lid covered with a biofilm in each formulation as a treatment solution. The pegged lid was then removed from the treatment solution and cultured overnight with whole human saliva to form a mixed-species saliva-induced biofilm. The amount of biofilm grown on each pegged lid was quantified by measuring ATP using a bioluminescence reaction and on the pegged lid exposed to a negative control (Sample J) of benzoic acid / ethanol solution. Compared to the amount of biofilm grown. The results were reported as logarithmic values of RLU. The lower value corresponds to a smaller amount of biofilm. The logarithmic values of the obtained RLU are shown in Table 1.

Example 2: Examination of different ratios and concentration ranges of succinic acid / trans-aconitic acid Succinic acid and trans-aconitic acid were blended as a total mouse rinse formulation, and their concentrations and ratios were systematically changed. The amounts and materials of each formulation are shown in Tables 2-5. Each formulation containing succinic acid, trans-aconitic acid, and both succinic acid and trans-aconitic acid was prepared. The total concentrations of succinic acid and trans-aconitic acid used in each of the formulations shown in Tables 3-6 are 10.5 mM, 21 mM, 42 mM, and 63 mM (ie 0.12 wt% to 1.1 wt), respectively. %)Met. These formulations were prepared by dissolving water-soluble components in water, including succinic acid, trans-aconitic acid, poloxamer 407, sodium lauryl sulfate, sodium benzoate, saccharin, sucralose, sorbitol, and FD & C Green No. 3. .. Separately, all water-insoluble ingredients including menthol, thymol, eucalyptus, methyl salicylate, flavoring agents, and benzoic acid were dissolved in propylene glycol. Then, this propylene glycol solution was added to the above aqueous solution and mixed.

The effect of each formulation was tested using two methods. The first method is "Multi-Treatment Static Biofilm with Pretreatment Assay Method", and the second method is "Prevention Assay Method". ". These test methods are described below.

Pre-treated multi-treatment static biofilm assay Each formulation was prepared using conventional mixing techniques in the same manner as described above. The pH of each formulation was about pH 4.2. Plates with polystyrene pegs (96 pegs, N = 8 / group) were exposed to saliva for 30 minutes to form a biofilm on each peg at a temperature of 35 ° C. Eight pegs (N = 8) for each formulation were then pretreated with the formulations at room temperature for 10 minutes using an orbital shaker set at 500 RPM. As a negative control, 8 pegs (N = 8) were pretreated with sterile water for 10 minutes. A 24-hour saliva biofilm was then grown on these polystyrene pegged plates at a temperature of 35 ° C. Each peg was then reprocessed with the same formulation for 30 seconds at room temperature using an orbital shaker set at 500 RPM (N = 8). This reprocessing was performed twice a day for 2 days, and a total of 6 treatments including the pretreatment were performed.

After all treatments were completed, the biofilm from each peg was neutralized and rinsed. Biofilms were harvested by sonication using a Q-Sonica Q700 sonic liquid treatment system (Q-Sonica, Newtown, CT) equipped with a 431MP4-00 microplate horn damper and a 0.5: 1 reverse gain booster. .. Adenosine triphosphate (ATP) released from the lysed bacteria after lysing the bacteria with Celsis Luminex using the Celsis Rapid Detection RapiScreen kit (Celsis International PLC, Chicago, IL) is used as a bioluminescence marker Celsislumin. Measurements were made using a Centro LB960 microplate luminometer supplied by Berthold Technologies (Wildbad, Bacteria). The data were reported as log RLU (RLU). A low log RLU indicates that there are few surviving bacteria remaining on the biofilm substrate.

Prophylactic Assay Each formulation was prepared as described above using conventional mixing techniques. The pH of each formulation was about pH 4.2. A plate with polystyrene pegs coated with hydroxyapatite (96 pegs, N = 8 / group) was exposed to saliva for 1 minute to form a biofilm at a temperature of 35 ° C. Eight pegs (N = 8) for each formulation were then pretreated with the formulation for 10 minutes at room temperature using an orbital shaker set at 500 RPM. As a negative control, 8 pegs (N = 8) were pretreated with sterile water for 10 minutes. The saliva biofilm was then grown on these polystyrene pegged plates for 16 hours at a temperature of 35 ° C.

After all treatments were completed, the biofilm from each peg was neutralized and rinsed. Biofilms were harvested by sonication using a Q-Sonica Q700 sonic liquid processor (Q-Sonica, Newtown, CT) equipped with a 431MP4-00 microplate horn damper and a 0.5: 1 reverse gain booster. .. Adenosine triphosphate (ATP) released from the lysed bacteria after lysing the bacteria with Celsis Luminex using the Celsis Rapid Detection RapiScreen kit (Celsis International PLC, Chicago, IL) is used as a bioluminescence marker Celsislumin. Measurements were made using a Centro LB960 microplate luminometer provided by Berthold Technologies (Wildbad, Bacteria). The data were reported as log RLU (RLU). A low log RLU indicates that there are few surviving bacteria remaining on the biofilm substrate.

Table 6 summarizes the results of the "static biofilm assay with multiple pretreatments" and "preventive assay" for each of the formulations.

1 and 2 show a plurality of formulations A21 to L21 containing succinic acid (SA) and trans-aconitic acid (tAA) shown in Table 3 above with respect to the reduction rate (%) of bacterial adhesion (relative to water). It is a plot of the removal rate (%) (relative to water) of the biofilm after each treatment. The broken line in the figure is the predicted result by the straight line of the blend of SA and tAA. In each figure, when succinic acid and trans-aconitic acid are combined in a ratio of 0.9: 1-14.1: 1 (succinic acid: trans-aconitic acid), the results are surprisingly different from the expected results. Is shown.

Table 6 shows similar surprising results when examining the distance from the expected results of the blend of succinic acid and trans-aconitic acid for other concentrations of the combined acid substances in the table.

Example 3: Biofilm Preventive Performance of Compounds Each of the formulations A2 to J2 shown in Table 7 was prepared and tested in a biofilm preventive assay. Each formulation was tested in an in-vitro static multi-treatment mixed species biofilm assay. The pegged lid covered with the mycelium was pretreated with each formulation before growing the biofilm. The treated pegged lid was then cultured with whole human saliva for 24 hours to form a mixed-species saliva-induced biofilm. The biofilm was treated with each formulation twice daily for 60 hours, a total of 5 times for 30 seconds. The results are reported as the log RLU of RLU and are shown in Table 7. The lower value corresponds to a smaller amount of biofilm. The results were then used to create an outer surface that maximized activity with different concentrations of succinic acid and trans-aconitic acid. A positive control (Sample J2) containing a standard essential oil containing a mouse rinse was also prepared and tested.

注：滅菌水のＬｏｇ ＲＬＵは７．３９であった。

Note: The Log RLU of sterile water was 7.39.

[Implementation]
(1) A method for inhibiting a biofilm, which comprises applying a composition containing succinic acid, aconitic acid, and a carrier to a surface having a biofilm, wherein the succinic acid and aconitic acid have the composition. A method in which the ratio of succinic acid to aconitic acid is present in the substance at a ratio of about 0.9: 1 to about 40: 1.
(2) The method according to the first embodiment, wherein the surface is the surface of the oral cavity.
(3) The method according to embodiment 2, wherein the surface of the oral cavity is selected from the group consisting of one or more tooth surfaces, gingival surfaces, and a combination of two or more thereof.
(4) The method according to embodiment 3, wherein the composition has a ratio of succinic acid to aconitic acid of about 0.9: 1 to about 20: 1.
(5) The method according to embodiment 3, wherein the composition has a ratio of succinic acid to aconitic acid of about 0.9: 1 to about 14: 1.

(6) The method according to embodiment 3, wherein the composition has a ratio of succinic acid to aconitic acid of about 0.9: 1 to about 9: 1.
(7) The method according to embodiment 3, wherein the total measurement of succinic acid and aconitic acid in the composition is about 0.1 to about 2% by weight of the composition.
(8) The method according to embodiment 3, wherein the total measurement of succinic acid and aconitic acid in the composition is about 0.1 to about 1% by weight of the composition.
(9) The method according to embodiment 3, wherein the total measurement of succinic acid and aconitic acid in the composition is about 0.1 to about 0.5% by weight of the composition.
(10) The method according to embodiment 3, wherein the total measurement of succinic acid and aconitic acid in the composition is about 0.1 to about 0.3% by weight of the composition.

(11) The method of embodiment 3, wherein the composition is applied to the surface in the form of mouthwash or mouth rinse.
(12) The method according to embodiment 3, wherein the composition is applied to the surface in the form of toothpaste.
(13) The method of embodiment 3, wherein the applied step comprises contacting the surface for less than 30 seconds.
(14) The method according to embodiment 3, wherein the applied step comprises contacting the surface for 30 seconds or longer.
(15) The method according to embodiment 3, wherein the aconitic acid is trans-aconitic acid.

(16) The method of embodiment 3, wherein the carrier comprises a water / alcohol mixture.
(17) The method according to embodiment 3, wherein the composition contains an amount of alcohol in an amount of about 10% by volume or less of the total composition.
(18) The method according to embodiment 3, wherein the composition does not contain alcohol.
(19) The method according to embodiment 3, which comprises removing the biofilm from the surface.
(20) The method according to the third embodiment, which comprises reducing bacterial adhesion to the surface.

Claims (3)

A composition for use in a method of inhibiting a biofilm, wherein the method comprises applying the composition to a surface having the biofilm, wherein the composition comprises succinic acid, aconitic acid and a carrier. The succinic acid and the aconitic acid are present in the composition in a ratio of succinic acid to aconitic acid of 0.9: 1 to 14: 1.
The surface is the surface of the oral cavity
The surface of the oral cavity is selected from the group consisting of one or more tooth surfaces, gingival surfaces, and combinations of two or more thereof.
A composition in which the composition is applied to the surface in the form of mouthwash or mouth rinse. A composition for use in a method of inhibiting a biofilm, wherein the method comprises applying the composition to a surface having the biofilm, wherein the composition comprises succinic acid, aconitic acid and a carrier. The succinic acid and the aconitic acid are present in the composition in a ratio of succinic acid to aconitic acid of 0.9: 1 to 14: 1.
The surface is the surface of the oral cavity
The surface of the oral cavity is selected from the group consisting of one or more tooth surfaces, gingival surfaces, and combinations of two or more thereof.
A composition in which the composition is applied to the surface in the form of a toothpaste. A composition for use in a method of inhibiting a biofilm, wherein the method comprises applying the composition to a surface having the biofilm, wherein the composition comprises succinic acid, aconitic acid and a carrier. The succinic acid and the aconitic acid are present in the composition in a ratio of succinic acid to aconitic acid of 0.9: 1 to 14: 1.
The surface is the surface of the oral cavity
The surface of the oral cavity is selected from the group consisting of one or more tooth surfaces, gingival surfaces, and combinations of two or more thereof.
A composition in which the composition contains an amount of alcohol in an amount of about 10% by volume or less of the total composition.

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